Tony Hagen

GENETIC ABNORMALITIES PLAY A role in multiple myeloma — and better understanding of them will improve outcomes, particularly for high-risk patients, said Shaji K. Kumar, M.D., a professor of medicine and chair of the Myeloma, Amyloidosis, Dysproteinema Group at Mayo Clinic in Rochester, Minn., during his talk at the 35th Annual CFS®.

“Over the years, as we have understood the biology of this disease better, it has become more clear that myeloma is not just one disease, and as multiple myeloma has become richer, so to speak, the divide between the rich and the poor has become even wider,” he said in reference to subgroups of patients for whom there are and are not effective treatment strategies.

“We still have over a quarter of these patients who are dying within the first three years,” even though median overall survival for patients with multiple myeloma is now eight to 10 years and improving, Kumar said. Targeting translocations, trisomies and chromosomal deletions is the key to superior outcomes, he added: “What is clear is that when patients have one or more of these abnormalities, their outcome is much poorer compared with the remaining patients.”

Fluorescence in situ hybridization (FISH) — a technique researchers use to visualize and map the genetic material in an individual’s cells &mdash; continues to be useful for diagnosing underlying causes of tumor growth, but there is a need for greater clarity in characterization of disease drivers for an appropriate therapeutic response, Kumar said.

“Unfortunately, FISH isn’t the answer to everything. It’s the most easily accessible test that we have,” he said. “The problem with the FISH testing is we all have patients now in our practice who may have del(17p) (a chromosomal deletion) or the t(4;14) translocation (a chromosomal translocation) who do much better than what we would have expected them to, and the reverse is also true.”

This has created huge interest in developing techniques that may be more specific in identifying patients with highrisk myeloma. These are necessary to tailor therapy according to intensity of duration and specific agents, which cannot be so easily accomplished on FISH alone, Kumar said.

FISH can effectively be used in conjunction with the International Staging System and other tests, such as gene expression-based classifications, which include a 70-gene prognostic signature, developed by the University of Arkansas for Medical Science, and a 92-gene signature test from SkylineDX, a Dutch molecular diagnostics company, he said.

Recent efforts to sequence the genome of relapsed multiple myeloma helped identify the most common mutations, such as KRAS and NRAS, some of which also have prognostic value. Involvement of del(17p) and mutated DNA repair genes can portend outcomes, but sequencing also holds the promise of “being able to develop therapies that are specifically targeted toward the underlying mutations,” Kumar said.

Such initiatives could also help high-risk populations, such as patients with plasma cell leukemia, “although this is a very small proportion of patients with myeloma, their outcomes are extremely poor, and — even though they have improved a bit &mdash; we’re still looking at median or overall survival of less than two years,” he said.

Ten years ago, the resources for such disease was limited to alkylating agents, anthracyclines and corticosteroids. Today’s tool kit holds significantly more — and more effective &mdash; options. Proteasome inhibitors, immunomodulatory agents, histone deacetylase inhibitors and monoclonal antibodies are now at a physician’s disposal.

“We have a whole host of new therapies, so we have a choice. We need to find out what is the best combination of these different choices that could make a difference to these patients with high-risk multiple myeloma,” Kumar said.

Tailoring such therapies to fit the patient and disease state could involve using specific drugs or drug classes, combining drugs, varying therapy duration and targeting a particular level of response, such as complete response or minimal residual disease negativity.

Kumar provided a few examples of new approaches that are working, such as use of the proteasome inhibitor Velcade (bortezomib) in cases of t(4;14) translocation. “Both in the newly diagnosed and the relapsed setting, what has become clear is that when you treat patients with bortezomib for a long period of time, there seems to be a significantly improved outcome compared with what we have historically seen in these patients,” he said.

Tandem autologous stem cell transplants (ASCTs) in cases of del(17p) with or without t(4;14) also are promising, Kumar noted. At 48 months, 76 percent of patients were alive following tandem ASCT, as opposed to 33 percent for a single ASCT, following Velcade-based induction regimens, according to trial results published in 2013.

“These data also seem to be borne out by some of the more recent trials, which looked at tandem versus single transplants. There is some suggestion that patients with high-risk abnormalities do benefit from tandem ASCTs,” Kumar said.

Articles

Experts focus on genetic abnormalities to advance cancer care.

Better Outcomes in High-Risk Multiple Myeloma

Researchers find that women with postmenopausal hormone receptor (HR)-positive breast cancer may undergo shorter treatments of Arimidex, which may in turn cause less bone fractures.

Investigators with the Austria Breast and Colorectal Cancer Study Group announced today that years can safely be shaved off Arimidex (anastrozole) treatment without affecting disease-free survival (DFS) for women with postmenopausal hormone receptor (HR)-positive breast cancer.

Additionally, shorter treatment spans can significantly reduce bone fractures, a side effect of aromatase-inhibitor (AI) therapy.

Results from the ABCSG-16 phase III trial were presented at the 2017 San Antonio Breast Cancer Symposium held in San Antonio, Texas.

For years, oncologists have followed up initial AI therapy with extended therapy for up to five years. Michael Gnant, M.D., director and chairman, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, recommended that oncologists immediately incorporate the new findings into practice by significantly reducing the use of adjuvant AI therapy following initial treatment. “There is simply no rationale to keep most patients on extended AI for longer than two years,” said Gnant, the study’s lead author.

Investigators enrolled 3,484 postmenopausal women with HR-positive early-stage breast cancer from February 2004 to June 2010. The patients, all of whom had undergone an initial five years of adjuvant endocrine treatment, were randomly assigned to two years (n = 377) or five years (n = 380) of extended adjuvant therapy. About 50 percent of the enrolled patients had been treated initially with Soltamox (tamoxifen), and the remainder with AI or any sequence of Soltamox and AI. Median age was 64 years.

The primary endpoint of was DFS, and investigators observed little difference between the two groups. At 10 years from randomization, the DFS rates were 71.1 percent for the two-year group versus 70.3 percent for the five-year group.

As of June 30, 2016, 78 percent of women in both trial arms were alive without recurrence. Recurrence, relapse, or other DFS events were equally common in both groups (22 percent). Investigators said there was no significant difference in overall survival or time to contralateral breast cancer.

For women in the five-year adjuvant therapy arm, 6.3 percent had experienced bone fractures after five years on extended AI. In the two-year group, 4.7 percent had experienced fractures by the end of the five-year cutoff. There were 71 fractures in the two-year patient group (n = 1,556) versus 98 in the five-year cohort (n = 1571). Investigators concluded that longer treatment with Arimidex may be a risk factor for fractures.

Other side-effect reductions were noted for the two-year group, including a lower incidence of arthralgia.

Ten years following randomization, 85.3 percent of patients in the two-year arm were alive versus 84.9 percent of those in the five-year arm. There was no difference between an additional two and five years of Arimidex in terms of overall survival, time to contralateral breast cancer, and time to second primary cancer, all of which were secondary endpoints in the trial.

Some patients may still benefit from taking Arimidex for longer periods, Gnant cautioned. He added that future translational research using data and biomaterial from patients in the ABCSG-16 trial could be useful in identifying potential molecular factors that influence how patients respond to Arimidex.

Patients with HR-positive breast cancer bear a significant risk of relapse and so extended AI therapy has become the norm and remains necessary, Gnant said. “More than 50 percent of relapses occur after the first five years of follow-up in this type of breast cancer.” Although ABCSG-16 found that two years of Arimidex was as good as five, Gnant said that earlier studies had established that less than two years of AI extended treatment would not produce comparable efficacy.

“We can now conclude that after five years of standard adjuvant endocrine treatment, two additional years with AIs are sufficient as extended therapy,” he said. “There is no benefit in escalating endocrine treatment beyond seven years. While not providing outcome benefits, the extension of five additional years leads to increased side effects, including fractures, and thus should be avoided.”

Duration of Arimidex Treatment For Breast Cancer May Safely Be Shortened 

A trial to determine the value of Herceptin (trastuzumab) plus standard adjuvant chemotherapy in patients with low levels of HER2 protein has shown no significant efficacy, confusing investigators who launched the trial based on opposing results from two earlier studies.

The findings were presented today at the San Antonio Breast Cancer Symposium (SABCS).

In a slide presented by Louis Fehrenbacher, M.D., medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center, at the SABCS press conference, the invasive disease-free survival (IDFS) lines for both arms of the study — with and without Herceptin &mdash; were plotted on top of each other and a difference was virtually indistinguishable. Fehrenbacher said that the primary objective of improving IDFS was not met, neither were any of the secondary endpoints, and “no trends of efficacy were seen.”

“We could magnify this slide, you still couldn’t see a difference between those two arms whatsoever,” he said. “There was no hint of efficacy in any of the stratification variables.”

The five-year IDFS rate was 89.6 percent among the 1,640 patients who received Herceptin and 89.2 percent among the 1,630 patients who did not. Investigators said the findings were no different whether patients were subdivided by HER2 immunohistochemistry (IHC) level, extent of lymph node involvement or hormone receptor status.

Fehrenbacher noted that the event rate was essentially equal between the two groups — 134 for the chemotherapy arm and 130 for chemotherapy plus Herceptin. There were no statistically significant differences in the five-year estimates for recurrence-free interval, distant recurrent-free interval, and overall survival between those who received Herceptin and those who did not.

Although the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of Herceptin and chemotherapy demonstrated improved outcomes for patients with early stage HER2-low breast cancer, the study (NSABP B-47) is valuable because it makes clear that patients with this form of the disease “can unequivocally know that Herceptin is not a beneficial treatment for them,” Fehrenbacher said.

Herceptin can cause serious adverse effects such as cardiotoxicity, so these findings help ensure that patients are not treated unnecessarily, Investigators added.

A moderator for the press conference noted that although SABCS normally does not present negative findings from trials, an exception was made in this case because of the importance to the large number of patients whose test outcomes are HER2-low and for whom studies like this offer hope for potential treatment.

“It doesn’t answer the question completely, but certainly if there’s a high suspicion or increased suspicion, one can certainly test other areas of the tumor,” Fehrenbacher said.

Asked if changes in testing procedures over time may have contributed to the findings, Fehrenbacher said that, if anything, testing has gotten better, and in the case of B-47, the testing was tightened up to ensure higher quality results.

He said the results came as a surprise, particularly because of the sharpness of the demarcation between those who benefit from Herceptin and those who do not.

The combination use of Herceptin plus standard adjuvant chemotherapy does not improve outcomes in women with HER2-low breast cancer.

Negative Findings Show Herceptin Fails to Benefit Breast Cancer Subgroup

As PARP inhibitors continue to improve outcomes in patients with ovarian cancer, they may one day be moved into the frontline treatment setting, said Susana M. Campos, M.D., a gynecologic oncologist at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School.

“It’s important that we start to use these drugs more and more and bring them sooner into the management of the individual,” said Campos, who reviewed trial data and approvals for several PARP inhibitors and looked at the potential for advancing the use of these agents.

Various PARP inhibitors, which interfere with tumor cell ability to make DNA strand repairs, have been approved by the FDA for use following platinum therapy and for maintenance in the ovarian setting. Those include Lynparza (olaparib), for germline BRCA mutations (gBRCAm) following three prior lines of therapy; Rubraca (rucaparib), for gBRCAm and somatic BRCAm following two prior lines; and Zejula (niraparib) and Lynparza for post-platinum maintenance.

Several trials of these agents are important for the light they shed on PARP capabilities, Campos said. Those include NOVA, SOLO-2, STUDY 19 and ARIEL-3.

The NOVA trial applied Zejula in platinum-sensitive, recurrent, high-grade, serous carcinoma, in patients previously treated with at least four cycles of a platinum-containing agent who had shown response, partial or complete. Treatment dosage was 300 mg daily. In the gBRCAm cohort, the median progression-free survival (PFS) for Zejula was 21 months versus 5.5 months on placebo; and in the non-gBRCAm homologous repair defect (HRD)-positive cohort the median PFS was 12.9 and 3.8 months, respectively. In the overall non-gBRCAm group, the median PFS was 9.3 months on Zejula versus 3.9 for placebo.

“Niraparib improved PFS across all three groups—germline and nongermline,” Campos noted.

The SOLO-2 study was unique in that it accrued BRCA1 and BRCA2 mutation carriers only, she said. Patients had at least two prior lines of platinum therapy and had demonstrated sensitivity to platinum. Dosage was 300 mg twice daily. The Lynparza group (196 patients) had a median PFS of 19.1 months versus 5.5 months for those on placebo.

STUDY 19 enrolled patients with platinum-sensitive, high-grade serous ovarian cancer and at least two previous platinum regimens. Of 265 recruited, 22 percent were BRCA positive and 14 percent were BRCA negative. The rest were BRCA wild-type. Lynparza dosage was 400 mg orally, twice daily. Treatment was until disease progression. In the primary analysis, median PFS was 8.4 months for Lynparza and 4.8 months on placebo. Campos noted that what was particularly significant about this study was that it accepted all comers, whether they were BRCA carriers or not.

The ARIEL3 study was a phase 3 randomized trial of Rubraca versus placebo in patients with ovarian cancer who had responded to platinum therapy. In the BRCAm subgroup, median PFS was 16.6 months for Rubraca and 5.4 months on placebo; for patients in the HRD BRCA germline or somatic group, the median PFS was 13.6 versus 5.4 months; and in a third group that included germline or somatic BRCAm plus BRCA wild-type, the median PFS was 10.8 months for patients on Rubraca versus 5.4 months for those on placebo.

Although the trials produced striking efficacy data, “It’s also important to balance [treatment decisions] with knowledge of toxicity, and in truth all PARP inhibitors share some common toxicities in terms of gastrointestinal toxicities as well as hematological adverse events [AEs],” Campos said . Common AEs included anemia, neutropenia, and thrombocytopenia. “Thrombocytopenia was seen a bit frequently in the NOVA trial very early on, but it was clearly attenuated with a dose reduction, so that is quite important.”

“There are other toxicities that can be unique to one or two particular agents, and as you tailor these drugs to your patients, knowing these toxicities is extremely important.” Metabolic effects and drug-to-drug interactions are also important to understand, she noted.

“We want these drugs in the upfront setting,” and the question is whether past and ongoing trial activity will provide the necessary evidence for doing so, Campos said. In addition, there are other riddles that need to be solved, such as the workings of mechanisms of resistance to PARP inhibitors and whether PARP inhibitors can be used after PARP inhibitors. “The elephant in the room is how can testing strategies for BRCAm or non-BRCAm ovarian cancer be used to personalize treatment strategies?” she said.

Nevertheless, there’s enough ongoing trial activity to guarantee that some answers will emerge. “We often think of patients we could have given these drugs to many years ago and didn’t have them to give. It’s a very exciting time in the management of ovarian cancer,” Campos concluded.

Tony Hagen

Better Outcomes in High-Risk Multiple Myeloma

Duration of Arimidex Treatment For Breast Cancer May Safely Be Shortened

Negative Findings Show Herceptin Fails to Benefit Breast Cancer Subgroup

PARP Inhibitors Continue to Show Promise in Ovarian Cancer

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